Method and apparatus for diagnosis and treatment

ABSTRACT

Method and apparatus for performing multiple measurements and diagnoses include a data acquisition module, a data processing module, an optional treatment output module, a user control module, and a user display system, where the data acquisition module sends a plurality of measurement data simultaneously to the data processing module. The data processing module provides a plurality of outputs which can be made available to the user or combined in the diagnostic module. A treatment algorithm in the treatment module can affect the patient through a feedback mechanism. In response, the data processing module generates treatment information needed by the treatment output module. In one embodiment, the data acquisition module sends multiple different measurement data relating to one or more diseases to the data processing module. In response to further measurements of the parameters, an effectiveness of the treatment can be determined and the treatment regimen can be modified, as necessary.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/475,833, filed May 18, 2012, which is hereby incorporated byreference herein in its entirety.

U.S. patent application Ser. No. 13/475,833 is a continuation-in-part ofU.S. patent application Ser. No. 12/485,855, filed Jun. 16, 2009, whichclaims the benefit of U.S. Provisional Patent Application No.61/129,285, filed Jun. 16, 2008, each of which is hereby incorporated byreference herein in its entirety.

U.S. patent application Ser. No. 13/475,833 is also acontinuation-in-part of U.S. patent application Ser. No. 12/098,257,filed Apr. 4, 2008, which claims the benefit of U.S. Provisional PatentApplication No. 60/915,097, filed Apr. 30, 2007, and which is acontinuation-in-part of U.S. patent application Ser. No. 11/151,967,filed Jun. 14, 2005, which claims the benefit of U.S. Provisional PatentApplication No. 60/599,959, filed Aug. 9, 2004, each of which is herebyincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The invention relates generally to analysis methods and equipment, andin particular to measurement, diagnostic, and treatment equipment ableto perform any or all of the functions substantially simultaneously orin a prescribed order. It allows not only for immediate testing but alsofor long term monitoring of the disease, and for treatment in responseto such monitoring, as well as for monitoring of treatment efficacy,which can have importance both for personalized medicine and for drugdiscovery.

The equipment will allow a lab or doctor not only to diagnose thepatient (human or non-human (for example, a cow, sheep, horse, etc.) butalso to approach each patient's needs individually (effecting trulypersonalized medicine) in order to:

1) be able to identify a sub-population of patients who may not beappropriate candidates for a specific treatment, either due to apredicted lack of treatment efficacy, or due to potentially significantside effects for their biological make-up;

2) allow for appropriate individual treatment dose and delivery scheme,based not only, for example, on the patient's age and weight, but alsoon biomarkers and other measured analytes; and

3) allow for a combination of drugs (in appropriate doses), based on theindividual patient's test results.

The invention also relates generally to delivery systems that transportsubstances (e.g., drugs, fluids, etc.), where the delivery may beadjusted and controlled using a feedback mechanism.

BACKGROUND OF THE INVENTION

The medical device field for measurement, analysis, and treatment of thehuman (and non-human) condition has grown substantially over the pastyears as the ability to build customized equipment, easily and quicklyusing specialized chips has enabled both large and small companies toenter the field. Of particular interest has been the use of so-called“biomarkers”, each of which can be defined to represent a specificmeasurement or series of measurements, representative of a specificcondition or function of the human body. Such biomarkers typicallyrelate to a biological condition, state, or function, but notmeasurements of seemingly unrelated parameters such as blood gases(e.g., pO₂, pCO₂), pH, electrolytes, temperature, measured bodilyelectrical signals (e.g., EKG, EEG, EMG), etc.

Substantial quantities of data relating to biomarkers and otherparameters regarding the human condition such as blood gases, pH,electrolytes, temperature, electrical signals and the like have beencollected for many specific diseases of the body. Also automatic testequipment has been marketed and has been, typically, measurement driven.Equipment is available for measuring pH, oxygen, and temperature atvarious parts of the body, and various biological measurement schemawhich are intended to measurement, for example, sugar levels, blood cellcounts, the presence of various genes, proteins, acids, etc., and so onare also available. Such equipment is available from many differentvendors and provides in many cases, excellent results for themeasurement for which they were designed. It is then, typically, up tothe doctor or an automated analysis device, which is used by the lab orthe doctor and into which selected data is provided, as requested by thedoctor, to provide a diagnosis of the patient.

Similar advances are being made in connection with non-human measurementand analysis, as well as in the measurement and analysis ofenvironmental “parameters” (for example, quality of water) in an effortto improve and automate the analysis and resulting diagnosis andconclusions relating to the input data.

SUMMARY OF THE INVENTION

In accordance with some embodiments of the present invention, methodsand apparatus for diagnosis and treatment are provided.

In some embodiments, an apparatus for performing multiple diagnosticssimultaneously, in terms of body function, is provided, the apparatuscomprising: a data acquisition module; a data processing moduleconnected to the data acquisition module; a treatment output moduleconnected to the data processing module; a user control module connectedto the data processing module; a user display system connected to thedata processing module; and said data acquisition module sending aplurality of measurement data simultaneously, in terms of bodyfunctions, to said data processing module, and in response thereto, thedata processing module generates patient information needed by thetreatment output module.

In some embodiments, the apparatus further comprises: said dataprocessing module being responsive to said user control module forgenerating said patient information and for generating user displayinformation for use by the user display system.

In some embodiments, the apparatus further comprises: said dataacquisition module sends the plurality of the measurement data relatingto a single disease to said data processing module.

In some embodiments, the apparatus further comprises: measuring modules,connected to said data acquisition module, comprising one or more of:one or more biomarker sensors, a pH sensor, a pO₂ sensor, aspectrometer, an optical sensor, and an electrical measurement system, achemical measurement system, a physical measurement system, and anelectrochemical measurement system.

In some embodiments, a method for performing multiple diagnostics isprovided, the method comprising: simultaneously, in terms of bodyfunctions, measuring, using a data acquisition module, a plurality ofparameters relating to diagnosis or treatment of a disease; in responseto said measured parameters, determining said diagnosis or treatment ofsaid disease; and effecting a treatment regimen based on said determineddiagnosis or treatment.

The method further comprises: selecting a plurality of the parameters tomeasure in response to a user input, and displaying to said user, adiagnosis and a basis therefore.

The method further comprises: in response to further measurements ofsaid parameters, determining an effectiveness of said treatment, andmodifying, as necessary, said treatment regimen; and monitoring, on anon-going basis, the effectiveness of said treatment.

In some embodiments, an apparatus for performing multiple diagnosticssimultaneously, in terms of body function, is provided, the apparatuscomprising: a data acquisition module; a data processing moduleconnected to the data acquisition module; a user control moduleconnected to the processing module; and said data acquisition modulesending a plurality of measurement data simultaneously, in terms of bodyfunctions, to said data processing module, and in response thereto, thedata processing module generates patient information.

In some embodiments, the apparatus further comprises: a treatment outputmodule connected to the data processing module.

In some embodiments, the method further comprises, in response to saidfurther measurements of said parameters, modifying, as necessary, saidtreatment regimen.

In some embodiments, an apparatus for simultaneously performing multiplediagnostics is provided, the apparatus comprising: a diagnosticapparatus that performs multiple diagnostics on one or more diseases andthat receives a plurality of inputs, wherein the diagnostic apparatuscomprises: one or more data acquisition modules that receive at leastone of: biomarker data and data from one or more other measurements; andone or more data processing modules connected to the one or more dataacquisition modules that receive at least a portion of the data from thedata acquisition module, wherein the data processing module responsivelygenerates patient information relating to a patient based at least inpart on the received portion of the data.

In some embodiments, the data processing module transmits the patientinformation to one or more of: a treatment output module for effecting atreatment, an external database for storage, and an external display.

In some embodiments, the apparatus further comprises: a communicationsmodule that communicates with the external database for at least one of:receiving the patient information, storing the patient information, andmanaging the patient information.

In some embodiments, the biomarker data is derived using spectroscopy.In some embodiments, the spectroscopy is selected from at least one of:fluorescent spectroscopy, mass spectroscopy, Raman spectroscopy, andFourier transform infrared spectroscopy.

In some embodiments, the data is measured in real time andsimultaneously.

In some embodiments, the one or more other measurements are receivedfrom at least one of: a pH sensor, a pO2 sensor, an optical sensor, anelectrical measurement system, a chemical measurement system, a physicalmeasurement system, and an electrochemical measurement system.

In some embodiments, a plurality of data acquisition modules receivesthe data from a plurality of inputs and transmits the portion of thereceived data to a plurality of data processing modules, and whereineach of the plurality of data processing modules transmits the portionof the data to a single processing module for subsequent processing.

In some embodiments, the apparatus further comprises a wirelesscommunications module that communicates with an external device. In someembodiments, the wireless communications module is configured totransmit the data and the generated patient information to the externaldevice for displaying status of the patient.

In some embodiments, the apparatus further comprises an externalanalysis device for diagnostic processing based on the generated patientinformation.

In some embodiments, an apparatus for effecting treatments uponperforming one or more diagnostics is provided, the apparatuscomprising: a treatment apparatus that effects a treatment regimen,wherein the treatment apparatus comprises: a treatment output moduleconnected to a data processing module that receives patient information,wherein the patient information is derived from at least one of:biomarker data and data from one or more other measurements and whereinthe treatment output module generates treatment information based atleast in part on the patient information; and a feedback moduleconnected to the data processing module that receives at least one of:updated biomarker data and updated data from the one or more othermeasurements, wherein the feedback module automatically controls atleast one of drug delivery, electrical signal parameters, and treatmentprotocols in response to the updated data.

In some embodiments, the biomarker data is derived from spectroscopy. Insome embodiments, the spectroscopy is selected from at least one of:fluorescent spectroscopy, mass spectroscopy, Raman spectroscopy, andFourier transform infrared spectroscopy. In some embodiments, the one ormore other measurements are received from at least one of: a pH sensor,a pO2 sensor, an optical sensor, an electrical measurement system, achemical measurement system, a physical measurement system, and anelectrochemical measurement system.

In some embodiments, the apparatus further comprises a communicationsmodule that communicates with an external database for at least one of:receiving the patient information, receiving the treatment protocols,receiving the treatment information, storing the patient information,storing the treatment information, managing patient information,managing the treatment information, and managing the treatment.

In some embodiments, the communications are conducted using a secureprotocol. In some embodiments, the external database provides at least aportion of the patient information and wherein the treatment outputmodule uses the portion of the patient information for generating thetreatment information.

In some embodiments, the apparatus further comprises a wirelesscommunications module that communicates with an external device. In someembodiments, the wireless communications module is configured totransmit at least one of: the data, the updated data, the patientinformation, and the generated treatment information for display. Insome embodiments, the wireless communications module and the externaldevice are configured to allow a user to manually control at least oneof drug delivery, electrical signal parameters, and treatment protocols.

In accordance with some embodiments of the present invention, electronicdelivery systems and methods with feedback are provided.

In some embodiments, a system for delivering a substance in a medium isprovided, the system comprising: a delivery component that includes atleast one reservoir, wherein the at least one reservoir contains thesubstance; an electronic controller that is connected to the deliverycomponent and that controls the release of the substance from the atleast one reservoir into the medium; and a sensing mechanism thatmonitors at least one parameter in the medium and that provides a signalto a feedback mechanism, wherein the feedback mechanism sends anelectrical control signal to the controller to effect the release of thesubstance from the at least one reservoir into the medium.

In some embodiments, the electronic controller further comprises: atleast one signal generator for generating a plurality of signals,wherein each signal has a controllable waveform based on at least oneelectrical parameter, and wherein the at least one electrical parameterincludes any of: amplitude, frequency, shape, timing parameters, phase,pulse duration, and pulse repetition rate; a selection mechanism forselecting as output signals one or more of the plurality of generatedsignals; and at least one output terminal, wherein the electroniccontroller is configured to place at least one of the output signals onthe at least one output terminal and wherein the output signals controlthe release of the substance from the at least one reservoir.

In some embodiments, the sensing mechanism comprises any of sensingelectrodes, pickup coils, temperature sensitive devices, magneticprobes, biosensors, and biomarkers.

In some embodiments, the electronic controller is further configured tocompare the monitored parameter to a desired value for the at least oneparameter. In some embodiments, the desired value is one of an upperlimit and a lower limit for the monitored parameter.

In some embodiments, the system is one of an electronic component, anintegrated circuit, a multi-chip module, a hybrid circuit, asystem-on-chip (SoC), a system-in-package (SiP), and a lab-on-a-chip.

In some embodiments, the controller is further configured to send anelectrical control signal that effects the release of a given volume ofthe substance from the at least one reservoir.

In some embodiments, the controller is further configured to send anelectrical control signal that effects the release of the substance fromthe at least one reservoir for a given time sequence or time pattern.

In some embodiments, in response to the sensing mechanism detecting thatthe concentration of the substance in the at least one reservoir isgreater than a desired value, the electronic controller is configured tosend an electrical control signal that effects the release of anothersubstance into the at least one reservoir that dilutes the substance.

In some embodiments, in response to the sensing mechanism detecting thatthe dosage of the substance in the at least one reservoir is greaterthan a desired value, the electronic controller is configured to send anelectrical control signal that effects the amount of the substance thatis released from the at least one reservoir.

In some embodiments, the at least one parameter comprises any of pH,pO₂, volume, pressure, temperature, ion, dosage, time, impedance, and abiomarker.

In some embodiments, the system is a drug delivery system.

In some embodiments, a system for delivering substances in a medium, thesystem comprising: a delivery component that includes a plurality ofreservoirs, wherein each of the plurality of reservoirs contains asubstance; a controller that is connected to the delivery component,wherein the controller comprises: at least one signal generator forgenerating a plurality of signals, wherein each signal has acontrollable waveform based on at least one electrical parameter, andwherein the at least one electrical parameter includes any of:amplitude, frequency, shape, timing parameters, phase, pulse duration,and pulse repetition rate; a selection mechanism for selecting as outputsignals one or more of the plurality of generated signals; and aplurality of output terminals, wherein the controller is configured toplace at least one of the output signals on each of the output terminalsand wherein the output signals control the release of the substance fromthe plurality of reservoirs; a sensing mechanism that monitors at leastone parameter in the medium; and a feedback mechanism that directs thecontroller to effect the release of at least one of the substances fromthe plurality of reservoirs into the medium based at least in part onthe monitored parameter.

In some embodiments, the controllable waveform comprises pulses.

In some embodiments, the at least one parameter comprises any of pH,pO₂, volume, pressure, temperature, ion, dosage, time, impedance, and abiomarker.

In some embodiments, the controller further comprises a combiningmechanism for combining two or more generated signals to provide theoutput signal.

In some embodiments, the sensing mechanism comprises any of sensingelectrodes, pickup coils, temperature sensitive devices, magneticprobes, biosensors, and biomarkers.

In some embodiments, the system is one of an electronic component, anintegrated circuit, a multi-chip module, a hybrid circuit, asystem-on-chip (SoC), a system-in-package (SiP), and a lab-on-a-chip.

In some embodiments, the plurality of signals are identical and whereinthe controller is further configured to place each of the plurality ofidentical signals on each of the plurality of output terminals.

In some embodiments, the controller is capable of synchronizing theplurality of identical signals.

In some embodiments, the controller is arranged to independently placeeach of the signals on the output terminals such that each signal oneach of the output terminals is independent from signals on each of theother output terminals.

In some embodiments, the controller is capable of synchronizing theplurality of independent signals.

In some embodiments, the controller is arranged to independently placeeach of the signals on the output terminals such that at least one ofthe signals on an output terminal is independent from another signal onanother output terminal.

In some embodiments, the controller is capable of synchronizing the atleast one signal and the another signal.

In some embodiments, the substance in one of the reservoirs is identicalto the substance in each of the other reservoirs.

In some embodiments, the substance in one of the reservoirs is differentfrom the substance in each of the other reservoirs.

In some embodiments, the substance in one of the reservoirs is differentfrom the substance in another reservoir.

In some embodiments, the controller is further configured to send anelectrical control signal that effects the release of a given volume ofthe substance from one of the plurality of reservoirs.

In some embodiments, the controller is further configured to: send afirst electrical control signal that effects the release of a firstvolume of a first substance from one of the reservoirs; and send asecond electrical control signal that effects the releases of a secondvolume of a second substance from another reservoir, wherein the firstelectrical signal and the second electrical signal are synchronized andwherein the first substance and the second substance are mixed.

In some embodiments, the controller is further configured to: send asequence of control signals for at least one of delivering and mixing aplurality of substances from said reservoirs.

In some embodiments, the controller is further configured to: send afirst electrical control signal that effects the release of a firstvolume of a first substance from one of the reservoirs; send a secondelectrical control signal that effects the releases of a second volumeof a second substance from another reservoir, wherein the firstelectrical signal and the second electrical signal are synchronized; andsend said control signals that effect the release of said substances inparallel or in sequence.

In some embodiments, the controller is further configured to send anelectrical control signal that effects the release of the substance fromone of the plurality of reservoirs for a given amount of time.

In some embodiments, in response to the sensing mechanism detecting thatthe concentration of the substance in at least one reservoir of theplurality of reservoirs is greater than a desired value, the controlleris further configured to send an electrical control signal that effectsthe release of another substance into the reservoir that dilutes thesubstance for a given time sequence.

In some embodiments, in response to the sensing mechanism detecting thatthe dosage of the substance in at least one reservoir of the pluralityof reservoirs is greater than a desired value, the controller is furtherconfigured to send an electrical control signal that changes the amountof the substance that is released from the at least one reservoir.

In some embodiments, a method for delivering a substance in a medium isprovided, the method comprising: receiving a signal from at least onesensor, wherein the at least one sensor monitors at least one parameterin the medium; and in response to receiving the signal from the at leastone sensor, transmitting an electrical control signal derived at leastin part from the at least one sensor to a controller to effect therelease of the substance from at least one reservoir into the medium.

In some embodiments, a method for delivering substances in a medium isprovided, the method comprising: providing a plurality of reservoirs;generating a plurality of signals, wherein each signal has acontrollable waveform based on at least one electrical parameter, andwherein the at least one electrical parameter includes any of:amplitude, frequency, shape, timing parameters, phase, pulse duration,and pulse repetition rate; selecting one or more of the plurality ofgenerated signals for use as output signals; providing multiple outputterminals, wherein at least one of the multiple output signals is placedon each output terminals and wherein the output signals control therelease of substances from the plurality of reservoirs; monitoring atleast one parameter in the medium; directing at least one controllerthat is connected to the plurality of reservoirs to effect the releaseof at least one of the substances from the plurality of reservoirs intothe medium based at least in part on the monitored parameter.

In some embodiments, the at least one parameter is a biomarker.

In some embodiments, a method for delivering a substance toectoderm-derived tissue is provided, the method comprising: receiving asignal from at least one sensor, wherein the at least one sensormonitors at least one parameter in the tissue; and in response toreceiving the signal from the at least one sensor, transmitting anelectrical control signal derived at least in part from the at least onesensor to a controller to effect the release of the substance from atleast one reservoir to the tissue.

In some embodiments, the method further comprises: (a) generating aplurality of signals, wherein each signal has a predetermined waveformand at least one of the signals comprises pulses; (b) adjusting one ormore electrical parameters of at least one signal, wherein theparameters include any of: amplitude, frequency, shape, timingparameters, phase, pulse duration, and pulse repetition rate; and (c)selecting as the control signal one or more of the generated andadjusted signals, wherein the selection is based upon an intendedapplication.

In some embodiments, the method further comprises: (a) sensing, usingone or more sensors, at least one measurable condition in the subjectand providing a sensor output; and (b) adjusting one or more electricalparameters of at least one signal responsive to the sensor output,wherein the parameters include any of: amplitude, frequency, shape,timing parameters, phase, pulse duration, and pulse repetition rate.

In some embodiments, the ectoderm-derived tissue is nervous tissue,comprising at least one of brain, spinal cord, optic, and peripheralnerves.

In some embodiments, the intended stimulation application isregeneration or repair.

In some embodiments, the intended stimulation application is pain relief

In some embodiments, the intended stimulation application is recovery ormaintenance of at least one of upper and lower extremity function,bladder, bowel, and erectile function, and respiratory function.

In some embodiments, a method for delivering a substance tomesoderm-derived tissue is provided, the method comprising: receiving asignal from at least one sensor, wherein the at least one sensormonitors at least one parameter in the tissue; and in response toreceiving the signal from the at least one sensor, transmitting anelectrical control signal derived at least in part from the at least onesensor to a controller to effect the release of the substance from atleast one reservoir to the tissue.

In some embodiments, the method further comprises: (a) generating aplurality of signals, wherein each signal has a predetermined waveformand at least one of the signals comprises pulses; (b) adjusting one ormore electrical parameters of at least one signal, wherein theparameters include any of: amplitude, frequency, shape, timingparameters, phase, pulse duration, and pulse repetition rate; and (c)selecting as the control signal one or more of the generated andadjusted signals, wherein the selection is based upon an intendedstimulation application.

In some embodiments, the method further comprises: (a) sensing, usingone or more sensors, at least one measurable condition in the subjectand providing a sensor output; and (b) adjusting one or more electricalparameters of at least one signal responsive to the sensor output,wherein the parameters include any of: amplitude, frequency, shape,timing parameters, phase, pulse duration, and pulse repetition rate.

In some embodiments, the mesoderm-derived tissue is at least one ofbone, circulatory system, muscle, and urinary system tissues.

In some embodiments, the intended stimulation application isregeneration or repair.

In some embodiments, the at least one measurable condition is abiomarker.

In some embodiments, the sensor output further comprises a comparison ofthe sensed measurable condition and a desired value or range of valuesfor the measurable condition.

In some embodiments, the method further comprises recording themonitored parameter and at least one of the amount, substance, and timeof the effected release.

In some embodiments, the method further comprises recording the sensedmeasurable condition and the adjusted electrical parameters.

In some embodiments, the method further comprises repeating themeasurement and comparing the new recorded information to the previouslyrecorded information, for at least one of diagnosis or treatment.

There has thus been outlined, rather broadly, the more importantfeatures of the invention in order that the detailed description thereofthat follows may be better understood, and in order that the presentcontribution to the art may be better appreciated. There are, of course,additional features of the invention that will be described hereinafterand which will form the subject matter of the claims appended hereto.

In this respect, before explaining at least one embodiment of theinvention in detail, it is to be understood that the invention is notlimited in its application to the details of construction and to thearrangements of the components set forth in the following description orillustrated in the drawings. The invention is capable of otherembodiments and of being practiced and carried out in various ways.Also, it is to be understood that the phraseology and terminologyemployed herein are for the purpose of description and should not beregarded as limiting.

As such, those skilled in the art will appreciate that the conception,upon which this disclosure is based, may readily be utilized as a basisfor the designing of other structures, methods and systems for carryingout the several purposes of the present invention. It is important,therefore, that the claims be regarded as including such equivalentconstructions insofar as they do not depart from the spirit and scope ofthe present invention.

These together with other objects of the invention, along with thevarious features of novelty which characterize the invention, arepointed out with particularity in the claims annexed to and forming apart of this disclosure. For a better understanding of the invention,its operating advantages and the specific objects attained by its uses,reference should be had to the accompanying drawings and descriptivematter in which there are illustrated preferred embodiments of theinvention.

DESCRIPTION OF THE DRAWING

Various objects, features, and advantages of the present invention canbe more fully appreciated with reference to the following detaileddescription of the invention when considered in connection with thefollowing drawings, in which like reference numerals identify likeelements.

FIG. 1A is a functional blocked diagram illustrating one particularembodiment of the invention.

FIG. 1B shows a schematic diagram of an illustrative system suitable fordelivering a substance (e.g., drugs, liquid, etc.) or electricalstimulation and having feedback capabilities in accordance with someembodiments of the present invention.

FIG. 2 is an illustrative block diagram of an exemplary electricalstimulation system having an ES stage, an output stage, and a measuringstage that may be used in accordance with some embodiments of thepresent invention.

FIG. 3 is an illustrative block diagram of a basic version of a systemfor producing various electrical stimulation pulses that may be used inaccordance with some embodiments of the present invention.

FIG. 4 is an illustrative example of a preset custom module that may beused in accordance with some embodiments of the present invention.

DETAILED DESCRIPTION

In the following description, numerous specific details are set forthregarding the methods and systems of the present invention and theenvironment in which such methods and systems may operate, etc., inorder to provide a thorough understanding of the present invention. Itwill be apparent to one skilled in the art, however, that the presentinvention may be practiced without such specific details, and thatcertain features which are well known in the art are not described indetail in order to avoid complication of the subject matter of thepresent invention. In addition, it will be understood that the examplesprovided below are exemplary, and that it is contemplated that there areother methods and systems that are within the scope of the presentinvention.

Diagnosis and Treatment

Mechanisms for diagnosis and treatment are described, for example, inU.S. patent application Ser. No. 12/485,855, filed Jun. 16, 2009, whichis hereby incorporated by reference herein in its entirety.

Embodiments of the invention relate to the design, use, and manufactureof a diagnostic apparatus able to perform multiple diagnostics, on thesame or different diseases, within a short period of time, in terms ofhuman body functions, instantaneously. The diagnostic equipment can usea front end, commercially available, to generate signals representativeof various bio-markers, as well as signals, from the same or differentsensing device (proprietary or commercial) representative of otherindicia, for example of the body, not considered biomarkers as that termis currently used. Multiple discrete sensing modules or a single sensingmodule can be used as the front end to receive sensor signals, and thesignals can be presented simultaneously or serially, to the sensingmodule(s), and then to a processing unit (for example, a digital signalprocessor (DSP)) which can be integrated into or separate from thesensing modules/devices or sensors. The analysis unit, that is, theprocessing unit, can have varying degrees of complexity, from a totallyflexible research analysis function, incorporating user controlled,powerful processing, to one or more customized units which may or maynot be user controllable, with their output being either a user definedvisual, printed, audio, digital, or other presentation or signal forcontrolling the delivery of diagnostic information or signals, forexample, for controlling the delivery of treatment directly orindirectly to or for the patient. The entire system can also bemanufactured on a chip which may be a custom chip, for example, anApplication Specific Integrated Circuit (ASIC), a chip preset for aclass of applications, for example, an Application Specific StandardProduct (ASSP), etc. The chip can be embedded in a patient, as part of atotally self-sufficient implantable device. It can also be connectedeither wired or wirelessly to an external viewing and communicationdevice (desktop, handheld, or PC) allowing for a manual control of allmeasured parameters and treatment regimens, a data dump to the externalmemory or PC, and additional analysis. It can be also wired orwirelessly connected to an analysis equipment for diagnostic processing,and can be integrated into a complete stand-alone system connected toreceive data from internal or external sources/sensors. The output ofthe chip can be interfaced with other electronic equipment, through anyappropriate protocol, including secure protocols for addressing privacyconcerns. While the apparatus of various embodiments can be manufacturedfor specific applications, that is, to check selected biomarkers andother signals for a specific disease or diseases, or other conditions,the apparatus can also interrogate a multiplicity of biomarkers, acrossseveral diseases to be examined, viewed, treated, etc., in order toprovide and improve treatment outcomes due to the immediate feedbacknature of the apparatus. Further, a standard set of biomarkers fitting aprofile for discovering or treating a specific disease can, ifappropriate, have added to it non-biomarker indicia which have theeffect of improving the accuracy of the diagnosis.

Tests comprising of these markers for, for example, coronary heartdisease may include cholesterol (HDL and LDL) and triglycerides combinedwith homocysteine and C-reactive protein (CRP), which is a generalmarker for inflammation and infection and PLAC testing, which incombination with LDL information is highly predictive of coronary heartdisease. In an acute situation, ischemia-modified albumin and bloodgases and ions will be of value. Roche Diagnostics, as an example, has acardiac reader analyzer which allows the quantitative determination oftroponin T, myoglobin, D-Dimer and now N-terminal proBNP (NT-proBNP)from a single whole blood sample within minutes.

Breast cancer tests may include CA 15-3 and CA 27.29 to follow-up breastcancer patients for reoccurrence of cancer, while ovarian cancer testsmay comprise a variety of markers depending on the type of the tumor.For example, in the case of epithelial tumors, tests may comprise acombination of CA-125 (cancer antigen 125), BRCA-1 and BRCA-2,carcinoembrionic antigen (CEA), galactosyltranferase, and tissuepolypeptide antigen (TPA). In the case of germ cell tumors, AFP (alphafeto protein) and quantitative hCG (human chorionic gonadotropin) can bemeasured, while for stromal tumors, Inhibin would be of interest.

In colon cancer, the fecal immunochemical test (FIT) or animmunochemical fecal occult blood test (iFOBT) are used. Stool DNA testlooks for abnormal sections of DNA instead of blood in the stool. Ifresults of those tests are positive, colonoscopy is required.Alternatively novel methods being developed by others rely on probemeasurements which would make colonoscopy unnecessary and which couldincorporate the invention.

The apparatus according to an embodiment of the invention can alsodiagnose, and/or treat as well as make measurements of, those bodilyindicia which on their face, are uncorrelated to each other. While notobviously thereby interconnected, these measurements may, when performedsubstantially simultaneously (in body time) to biomarker measurements,provide insight into the nature and the occurrence of diseases as wellas provide an advantage in treating diseases by correlating two or moreindicia, previously considered to be unrelated.

The additional measurements may include pO₂, pH, temperature, pressure,electrical signals (as noted above), etc. The apparatus, according toone embodiment, can also be connected to the Ethernet or Internet todownload the latest protocols, to update different levels of concern inregard to the medical measurement and diagnosis, and to provideadditional or different measurements in connection with a study, such aspatient data or images, for example, an MRI, CT scan, X ray.

The apparatus provides answers to the analytical questions based oninputs from biomarker and other non-biomarker signals. The analysis isprimarily based on the biological/biochemical markers but can be aidedby combination with non-biology input measurements such as electricalsignals (e.g., EKG, EEG, EMG), chemical, physical, electrochemical, etc.When connected in a feedback configuration, the apparatus can monitorthe results of treatment, in real time, to continuously orintermittently adjust and control the treatment delivery.

The invention thus relates to an apparatus for performing multiplediagnostics simultaneously, in terms of body function, having a dataacquisition module, a data processing module connected to the dataacquisition module, a treatment output module connected to the dataprocessing module, a user control module connected to the dataprocessing module, a user display system connected to the dataprocessing module, and wherein the data acquisition module sends aplurality of measurement data simultaneously, in terms of bodyfunctions, to the data processing module, and in response thereto, thedata processing module generates treatment information needed by thetreatment output module.

In another aspect, the invention relates to a method for monitoring,diagnosing, and/or treatment of a disease featuring simultaneously, interms of body functions, measuring, using a single data acquisitionmodule, at least five parameters relating to the diagnosis or treatmentof the disease, where in response to the measured parameters, the methoddetermines the diagnosis or treatment of the disease, and effects atreatment regimen based on the determined diagnosis or treatment.

In response to further measurements of the parameters, the methoddetermines an effectiveness of the treatment, and modifies, asnecessary, the treatment regimen.

Referring to FIG. 1A, a method and apparatus in accordance with aspectsof the invention include a system 10 having various modules orpartitions. The system 10 can be modeled after/or be the same as, inmany ways, the system on a chip described in U.S. patent applicationSer. No. 12/113,200, filed on Apr. 30, 2008, now U.S. Pat. No.7,937,683, entitled Method and Apparatus for Configurable Systems, thecontents of which are incorporated herein by reference in theirentirety.

Referring to FIG. 1A, again, the data processing element 12, for examplea digital signal processor, a custom data processor, or any other typeof data processing unit, acts as the central processing module for thesystem 10. In this embodiment, the processing element 12 connects to adata acquisition module 14, a treatment output module 16, a user controlmodule 18, and a user display system 20. At a high level, in operation,the data processing module 12 receives measurements and data in the formof, for example, biomarker and non-biomarker data from the dataacquisition unit, which is operating under the control of the dataprocessing element 12. The data processing element processes thatinformation, using, if appropriate, further information and datareceived from an external database or other external unit 22, and inresponse to user commands from a user control module 18 can generate, asrequired, both user display information for the user display 20 andtreatment information as needed for treatment module 16. If theapparatus is embedded in the patient, it can be connected by hard wiredcables, or wirelessly, continuously or intermittently, as necessary. Inthis exemplary configuration, a visual user display, for example, neednot be used or provided. It can be, however, connected preferablywirelessly to an external monitoring unit or PC for display of thepatient's status and for communication and manual control of the system,if required.

The data acquisition module 14 receives data from many differentsources, for generating biomarker information as well as non-biomarkerdata. Biomarkers may be associated for a particular disease, or for arange of diseases, or alternatively for a series of predefinedbiomarkers as dictated by the user. Methods such as genomics,proteomics, and/or molecular imaging, among other methods, can be usedin the generation of the biomarker information. Among specific methodsused, variety of spectroscopic methods can be applied, such asfluorescent spectroscopy, mass spectroscopy, which can be used, e.g.,for gene expression profiling, Raman spectroscopy and lately Fouriertransform infrared spectroscopy (RTIR). The various sources then,illustrated as source A, source B . . . source N, can be sources of dataassociated directly with measurements made in a patient, such as, forexample, temperature, pH, pO₂, etc. as described previously, for thenon-biomarker data or data provided directly from the patient or fromtest results relating to biological functions and useful for determiningbiomarker information. Such data can be obtained as described in theart, and, more particularly, as described in, for example, applicant'sU.S. Pat. Nos. 6,021,347, 6,029,090, 6,684,106, 6,708,066, 7,160,241,7,526,334, 7,517,311, 7,937,683, 8,365,122, and 8,595,672, U.S. pendingpatent application Ser. Nos. 11/063,195, 11/151,967, 11/213,050,12/098,257, 12/431,730, 12/485,855, 12/507,506, 13/085,366, 13/152,242,13/751,274, and 14/068,792, and International Publication No. WO2010/065678 A1, the disclosures of which are hereby incorporated byreference in their entireties.

Once the system operator has indicated which data to acquire and use, orwhich disease or diseases, or other conditions, to acquire data for, thedata processing system then operates upon that data, in connection withits own internal memory as well as memory available to it in the form ofexternal data or a database 22, to generate either user displayinformation in oral, written, or display form, or any other form, neededor required by the user, and/or further, upon user control of usercontrol module 18, the system can provide feedback, for example, to thepatient in the form of treatment. Such feedback, in the form oftreatment, allows for substantially automatic (or user controlled)feedback to regulate the delivery of drugs, or electronic signals, orother treatment protocols, which may then result in revised data fromdata acquisition module 14, thereby setting up a feedback control loopoperating in response to user control, and, if desired, viewable on userdisplay 20, as processed by data processing element 12 and implementedby the treatment module 16. Such treatment can be automatic (usingfeedback) and may be that described in the above-identified deliveryapplication U.S. Ser. No. 12/098,257, or in applicant's other relatedpatent applications, such as U.S. patent application Ser. No. 12/113,200filed on Apr. 30, 2008, now U.S. Pat. No. 7,937,683, the contents ofwhich are incorporated herein, in their entirety, by reference. Thesystem can be set up (including inputs, outputs and feedbacks), dataacquisition can be controlled, measurements can be processed, diagnosticor treatment algorithms can be applied and various communicationsschemes can be provided by, e.g., the systems described in patentapplication U.S. Ser. No. 61/119,244, filed on Dec. 2, 2008, the contentof which is incorporated herein, in its entirety, by reference.

Thus, treatments can be either manual and/or automatic, and made morepatient-related as the system reacts to the responsiveness andeffectiveness of the treatments, to modify the treatments. In thisregard, the signals from the external sources can be substantiallysimultaneous with regard to the human body's “time constant” for changeand thus, all measurements can be treated as made at the same time, solong as the measurement device does not adversely interact with themeasurement itself. In a specific embodiment, the measurements are madein real time and simultaneously. With such a substantial amount of dataavailable to the data processing element 12, the system can effectdiagnosis of patient concerns faster, and more accurately than priorsystems which were directed to a particular type of measurement andanalysis and small group of predetermined biomarkers which may or maynot relate to many or any specific diagnoses/diseases. In the currentapparatus, as described, the system can either collect a broad range ofbiomarker and non-biomarker information, substantially and preferablysimultaneously as defined herein, in order to process the data and yielda result which relates to a probable diagnosis relevant to a patient'sconcerns and complaints. Alternatively, if the diagnosis is to relate toa specific disease, for example, breast cancer, ovarian cancer, coronaryartery disease, or colorectal cancer, to name a few, a selected group ofbiomarker and non-biomarker measurements can be made, substantiallysimultaneously, in order to better diagnose the status of, and definethe treatment for, such a disease in the patient.

In operation, then, the system 10 initially operates to monitor anddefine, based on the inputs available to it, a disease, or provide adiagnosis through a specifically developed diagnostic algorithm. Theuser defines different inputs, typically available in parallel, usuallynot from the same sensing device, in a user-friendly manner andenvironment. The output is either a separate measurement or a set ofseparate measurements provided for each sensor/biomarker or a combineddiagnosis, based on the inputs available, which can be taken to the“next level” wherein a treatment regimen is determined and prescribed. Adisplay is provided illustrating the diagnosis and the basis therefor.Other information is provided to the user. In addition, information canbe provided to an internal and/or external database to provide betterpatient management for future efforts.

The resulting device can be used in different configurations for bothstandard and acute measurements and treatment, for example, in oneconfiguration for a yearly standard health screening and in another forthe emergency room, intensive care, or ambulance use. An additionalapplication area, with possibly specific configuration, could be foremergency situations on passenger air planes and at the airports, wheremedical personnel may not be available.

As noted above, the invention will also be useful with non-humanpatients, as well as in measuring and “treating” the environment. Inthat respect, the specifics of the measurements and their timing may bealtered depending upon the specific conditions being tested and treated.

Other objects, features and advantages of the invention will be apparentto those practiced in the field and are within the scope of theinvention.

Electronic Delivery Systems and Methods with Feedback

Electronic delivery systems and methods with feedback are described, forexample, in U.S. patent application Ser. No. 12/098,257, filed Apr. 4,2008, which is hereby incorporated by reference herein in its entirety.

In accordance with some embodiments of the present invention, deliverysystems and methods for delivering a substance in a medium, e.g., blood,saliva, other body fluids, muscle, etc., are provided.

In some embodiments, the delivery system includes a delivery componentthat includes at least one reservoir. The reservoir contains a substance(e.g., a liquid, a drug, etc.). The delivery system also includes anelectronic controller that is connected to the delivery component andthat controls the release of the substance from the at least onereservoir into the medium. The delivery system also includes a sensingmechanism (e.g., one or more sensors, one or more biomarkers, etc.) thatmonitors one or more parameters in the medium and provides a signal to afeedback mechanism. The feedback mechanism, in response to the signal,sends an electrical signal that directs the controller to effect therelease of the substance from the reservoir into the medium.

In another embodiment of the present invention, the delivery system mayinclude a delivery component that has a plurality of reservoirs. Acontroller that is connected to the delivery component includes a signalgenerator, a selection mechanism, and a plurality of output terminals.The signal generator generates a plurality of signals. Each signal has acontrollable waveform based on one or more electrical parameters (e.g.,amplitude, frequency, shape, timing parameters, phase, pulse duration,and pulse repetition rate). The selection mechanism selects as outputsignals one or more of the plurality of signals generated by the signalgenerator. The controller is also configured to place at least one ofthe output signal on each of the output terminals. It should be notedthat the output signals control the release of the substance from theplurality of reservoirs. It should also be noted that each reservoir maycontain a different substance. The delivery system may also include atleast one feedback mechanism that directs the controller to effect therelease of at least one of the substances from the plurality ofreservoirs into the medium.

Because the delivery system may be controlled by the controller and thefeedback mechanism, the delivery system is capable of precision mixingof various fluids or drugs (e.g., flow control of substances containedin multiple reservoirs), time delivery synchronization (e.g., dailydoses, intermittent, maintenance of treatment on a daily basis, oradminister the substance when needed, etc.), volumetric control ofsubstances, synchronization for multiple substances, diluting substancesfor providing the appropriate dose, controlling different ports, etc.

Generally speaking, the present invention is directed to methods andsystems for delivering substances (e.g., drugs, fluids, etc.), where thedelivery may be automatically controlled using an electrical stimulatorcomponent and/or a feedback mechanism.

The delivery system generally includes a waveform or pulse generatorcircuit (e.g., a digital pulse generator, an electrical stimulatorcomponent, etc.), one or more sensors, and at least one feedbackmechanism (e.g., a closed feedback loop, an open feedback loop, etc.).The sensors (e.g., physical sensors, chemical sensors, biochemicalsensors, etc.) detect and/or monitor various conditions in a medium(e.g., prevailing in the tissue, existing in a system, etc.) and providethe detected information to the feedback mechanism. In turn, thefeedback mechanism may direct the controller to perform an operation inresponse to the detected information (e.g., open a reservoir or releasea given amount of drugs using an electrical, mechanical, optical, orother signal). For example, the electrical stimulator component mayadjust the signal generated by the electrical stimulator component tomaintain an optimal operating or treatment condition. In particular, theelectrical stimulator component may adjust the signal generated tomaintain a given level of, e.g., ion, salt, pH, pO2, biochemical marker,volume, dosage, etc. or a gradient thereof. When used for treatment orother suitable biomedical applications, such an adjustment may optimizethe outcome of the treatment.

As used herein, “biochemical marker,” which may be used interchangeablywith “biological marker” or “biomarker,” refers to a characteristic thatis measured and evaluated as an indicator of a biological process (e.g.,a normal biological process, a disease or abnormal condition, or aresponse to a pharmacologic or other therapeutic treatment or procedurefor drug discovery). Such biomarkers may include, but are not limitedto, single nucleotide polymorphisms, gene expression patterns, proteins,peptides, and small molecule metabolites (e.g., glucose, cholesterol,phospholipids, amino acids, vitamins, etc.).

The delivery system of the present invention may be used for a number ofclinical applications, such as, for example, peripheral nerveregeneration, spinal cord regeneration, bone healing, wound healing,cancer treatment, cardiac rhythm management, an artificial pancreas,drug delivery, stem cell delivery, or pre-treated stem cell delivery(e.g., using the electrical stimulation systems to effect the stem cellsor gene therapy), in addition to the neurological and functionalelectrical stimulation applications.

In some embodiments, the delivery system may be used for bone healing.Electrical stimulation of bone healing has been used clinically for morethan about three decades. One approach for bone healing may includeusing implantable devices for both long bone healing and for spinalfusion. By controlling the electrical potential of the stimulatingelectrode (cathode) to be below the hydrogen evolution level, theoptimization of the bone formation process may be achieved. This may beaccomplished by measuring pH in the immediate vicinity of the cathode(which indicates if the hydrogen evolution takes place) and adjustingthe electrical potential of the stimulating electrode accordingly.

In another suitable embodiment, the delivery system may be used for theelectrochemical treatment of cancer. Prior methods that were developedoriginally in Sweden and used in treatment of thousands of patients inChina deliver electric current to solid superficial tumors via severalindwelled electrodes. The generated current destroys the tumor withoutany extensive bleeding by causing necrosis of the tissue andsignificantly changed pH values in the tissue. However, an improvedmethod for the electrochemical treatment of cancer may be provided byautomatically adjusting the electrode potential based at least in parton a measured pH value in the tissue to result in a smaller butsufficient pH changes to affect the tumor, thereby minimizing seriousnecrotic and inflammatory reactions.

It should be noted that, in some embodiments, electrical stimulation maybe provided on demand. Electrical stimulation may be used for tissueregeneration, for recovery or maintenance of function (e.g., upper andlower extremity function, bladder, bowel, and erectile function, andrespiratory function, which may be impaired in connection with, e.g.,spinal cord injury, stroke, head injury, cerebral palsy, or multiplesclerosis), as well as for cardiac rhythm management. In all of thosecases some disease-specific or therapeutic response-specific physical,chemical, or biochemical markers may be measured, resulting in on-demanddelivery of a specific sequence of an electric signal from an externalor implantable device. In the case of implantable devices, electricalstimulation may be administered as needed over a long period of time,initially to promote tissue regeneration or return of function and, at alater time, to maintain it.

In yet another suitable embodiment, the delivery system may be used toprovide controlled, active drug delivery. External or implantable drugdelivery systems may be automatically controlled by electrical signalsreceived in response to appropriate physical, chemical, or biochemicalmarkers continuously or intermittently monitored in the tissue. Awaveform generator may be used to control both the drug delivery timingsequences and a sensor measurement sequence, if intermittent. Sensorinformation may trigger the drug delivery mechanism, when, for example,the measured parameters fall outside of a given optimal value range(e.g., a preset optimal value range). For example, an example of aspecific application may be an insulin pump.

Alternatively, the delivery system of the present invention may be usedto deliver fluids or other suitable substances (e.g., through catheters,IV, or microfluidic channels). For example, the delivery system may befabricated or integrated onto a System-on-a-Chip (SoC). In addition,sensors, an electrical stimulator, a microprocessor (if needed) forcontrolling various components on the SoC, and/or any other suitablecomponent may be integrated onto the delivery system, which may beimplemented as a system on the chip.

For example, microfluidic devices may be used in printheads and othercomponents of an inkjet printer. The present invention may be used tocontrol the delivery of ink at the micron scale. As described above,each device may be electrically controlled using the delivery system ofthe present invention. In response to receiving an electric or opticalsignal a reservoir may open, allowing ink to flow through one of thechannels in the inkjet printhead. The system can be also used fordelivering antibodies, etc. for “diagnostic arrays” or “lab on a chip”.

In some embodiments, the delivery system of the present invention may beused in a high pressure liquid chromatography (HPLC) system. While HPLChas provided a separation tool capable of high resolution separations,rapid analysis, and high sensitivity, obtaining all the benefits thatHPLC offers typically requires careful attention to the flow portion ofthe HPLC system that carries the sample. Limitations on the performanceof the HPLC system are generally caused by problems with fluid transfer(e.g., dead volume, volume is different in certain columns, etc.). Inmany cases, the smallest amount of dead volume in the HPLC system maymake the difference between an acceptable separation and an unacceptableone. Dead volume dilutes chromatographic peaks, increasing their volumeand reducing chromatographic efficiency. Accordingly, the deliverysystem of the present invention may be used in a HPLC system to controlthe flow of fluids throughout the system, thereby reducing the amount ofdead volume in the HPLC system.

In some embodiments, the delivery system of the present invention may beused in a bioreactor. A bioreactor is generally a vessel or containedarea in which a chemical process that involves organisms orbiochemically active substances derived from such organisms is carriedout. In particular, the environmental conditions within the vessel ofthe bioreactor, such as gas (e.g., air, oxygen, nitrogen, carbondioxide), flow rates, temperature, pH, dissolved oxygen levels, andagitation speed need to be closely monitored and controlled. Thedelivery system may be integrated or connected to the bioreactor tomonitor and control the environmental conditions in the bioreactor.

It should also be noted that although the present invention is describedin terms of a delivery system, this is only one embodiment. The presentinvention may also be used in analytical instrumentation, in automatictest equipment, for drug discovery, or any other suitable application.

FIG. 1B shows a schematic diagram of an illustrative system suitable fordelivering a substance (e.g., drugs, liquid, etc.) or electricalstimulation and having feedback capabilities in accordance with someembodiments of the present invention. As shown in FIG. 1B, deliverysystem 100 includes a controller 102 (e.g., a microprocessor or anyother suitable processing device), a waveform generator 104, and asensor interface 106.

In some embodiments, delivery system 100 may also include memory 108 anda communication interface 110. Communication interface 110 may be anycommunication link suitable for communicating data between deliverysystem 100 and a computer (e.g., a workstation, PDA, laptop computer,cellular telephone, etc.), such as a network link, a dial-up link, awireless link, a hard-wired link, etc.

In some embodiments, waveform generator 104 may be a digital pulsegenerator Application Specific Integrated Circuit (ASIC). In someembodiments, waveform generator 104 may be an electrical stimulatorcomponent (sometimes referred to herein as an “ES component”) with oneor more output stages.

In general, an electrical stimulator component includes an ES signalstage having a selector coupled to a plurality of different signalgenerators, each producing a signal having a distinct shape such as asine, a square or sawtooth wave, or a simple or complex pulse, theparameters of which are adjustable in regard to amplitude, duration,repetition rate and other variables. The signal from the selectedgenerator in the ES stage is fed to at least one output stage where itis processed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.In some embodiments, also included in the system may be a measuringstage which measures and displays (if needed) the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substance,whereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type he wishes and the user can then observe theeffect of this signal on a substance being treated.

An electrical stimulator component or system in accordance with thepresent invention is shown in FIG. 2. The electrical stimulator systemis composed of an ES signal stage 10 which at the user's discretiongenerates a faradic, an electromagnetic, or other type of electricalstimulation signal which is fed to an output stage 11. Output stage 11processes the electrical stimulation signals selected by the user toyield a stimulation signal suitable for its intended biological orbio-medical application.

Also provided is a measuring stage 12 which measures and displays theelectrical stimulation signal operating on the biological substancebeing subjected thereto, and/or its electrical parameters as well as theoutput of various sensors which sense conditions prevailing in thissubstance whereby the user is able to observe, monitor as well as toadjust the effects of the stimulation signal he has selected on thesubstance being treated.

ES signal stage 10 includes signal generators 13 to 17 producing signalsof different shape. Generator 13 is a pulse wave generator generatingone or more rectangular pulses, such as pulses A and B of differentwidth which can be outputted separately or can be added or subtractedfrom each other to yield A or B, A plus B or A minus B. Generator 14 isa sine wave generator, generator 15 generates a triangular or sawtoothwave, and generator 16 produces a ramp voltage wave. Generator 17 yieldsa wave of any arbitrary shape. The signal generators are capable ofgenerating a minimum one pulsatory signal or a greater numbers ofpulsatory signals, or of generating a gated signal with a minimum of oneperiod or a greater number of periods, with individual adjustments ofelectrical parameters.

By means of a serial input port 18 to ES stage 10 or a set of parallelinput ports 19, the parameters of the respective waves produced bysignal generators 13 to 17 can be adjusted in frequency, pulse width,amplitude and repetition rate, or with respect to any other variable.Coupled to generators 13 to 17 and activated by a signal applied theretoat terminal 20A is a mechanical, electronic, or optical, etc. (e.g.,nanomaterial) selector switch 20. The output signal from the signalgenerator selected by a switch 20 is applied through a line 21 to outputstage 11. In practice, the line is preferably a bus system.

The ES signal stage 10 is preferably miniaturized and may take the formof a hybrid device or a single ASIC chip (Application SpecificIntegrated Circuit). Output stage 11 includes a mechanical, electronic,or optical selector switch 22 which applies the ES signal from stage 10either to a low voltage processor 23, a high voltage processor 24, acurrent processor 25, or a power processor 26 to put the ES signal in aform appropriate to the intended application for electrical stimulation.In a preferred version, all signals can be accessed simultaneously byone or more output stages through a system bus. In practice, acombination of one or more signal generators in the ES signal stage withone or more of the output stages can be miniaturized.

The output of the processor 23, 24, 25 or 26 chosen by selector switch22 is fed to a modulator 27 coupled to an amplitude control unit 28which modifies the amplitude of the signal applied thereto. (There arealso other ways to control the amplitude.) The output ofamplitude-control unit 28 is applied to a polarity control unit 29 inwhich the electrical stimulation signal is given a positive or negativepolarity or is converted to an AC signal, depending on the intendedapplication for the electrical stimulation signal.

Each output stage can be configured with either multiple outputterminals 30 or with a single output. The multiple outputs make itpossible to run several parallel experiments or processes concurrently.

As previously mentioned, the ES system can be miniaturized to form asingle ES component comprising signal generators and miniaturized outputcircuitry packaged together. A functional sketch of one such EScomponent 31 is shown in FIG. 3, and an example of a customized module32 with a preset waveform and preset electrical parameters is shown inFIG. 4.

A preferred version of the ES component includes a sophisticated digitalpulse generator on a chip and an analog circuitry to define complexpulse patterns, with amplitudes appropriate for a given application. Theoutput can be fed into any number of desirable output stages, which canbe integrated into the same component or be independent proprietarydevices, e.g., voltage controlled or current controlled output stageswith various voltage/current amplitudes, high frequency output stagewith various bandwidths depending on a specific application, variouspower output stages, etc. Waveforms other than pulse patterns, as wellas modulated signals can be part of such a “system on a chip.”

The design of a digital pulse generator (which can be implemented, e.g.,as an ASIC) consists of several blocks, which can be either usedtogether to create a sophisticated pulse generator for biomedicalapplications, or can be used in any number of other applicationsrequiring a pulse signal. Each of these blocks or functional modules canprovide an independent waveform or pulse (A pulse; B pulse; square wave;time delay; etc.). A basic one output version of the signal generatordelivers two independent pulses A and B with digitally adjustable pulsewidths, the same pulse repetition rate, and with an adjustable delaybetween them or for each of them. It also delivers a square wave andtiming for alternate and biphasic pulses and two pulse trains. In a twoor more output version, individual pulses can have independently setrepetition rates.

Several of these independent signal generators can be combined into amulti-output device. All timing parameters of the pulses preferably arefully programmable by a user via hardware or via software. For example,one can adjust timing using thumbwheels or switches connected viaparallel inputs of the ES component, or by using software and a serial,parallel, or custom interface as an input (or a combination of analogand digital inputs can be used). The ES component can include both aparallel and a serial interface so that the user can define the optimalmeans for each application.

The analog output amplitudes of the ES component or ES system can beadjusted for each pulse separately (via hardware or software, as above).At the same time, a specific DC level can be added; i.e., signal can beshifted up or down from zero line. The alternate and biphasic pulses aredesigned so that only one adjustment for both positive and negativepulse width and amplitude is required, which results in guaranteedsymmetrical signals.

Electric stimulator components, multi-functional systems, and methodsfor generating output signals are described, for example, inabove-mentioned U.S. Pat. No. 6,684,106, which is hereby incorporated byreference herein in its entirety.

Referring back to FIG. 1B, delivery system 100 may also include afeedback mechanism. One or more sensors may be connected to deliverysystem 100. The sensors may be used to measure and/or detect variousconditions prevailing in the tissue or any suitable medium. Sensorinterface 106 may include any component necessary to monitor and analyzedata received by the sensors. For example, as shown in FIG. 1, sensorinterface 106 includes signal conditioning circuitry and dataacquisition circuitry. In response to receiving a signal from a sensor,the feedback mechanisms may use the information relating to, forexample, the pH level, the pO2 level, the volume of drugs distributed,the drug dosage, timing parameters for drug delivery (e.g.,time-released, delayed release, etc.), or any other suitable parameterand direct the stimulator, the controller, or any other suitablecomponent of delivery system 100 to perform an operation. For example,the stimulator may use at least a portion of the information to adjustits signal accordingly to maintain an optimal level of measured entity(e.g., pH, pO2, ion concentration, biochemical marker, pressure,temperature, etc.) and to optimize the treatment outcome. In particular,the sensor capability and a feedback loop allow a user to measure or tomeasure automatically the effects of electrical stimulation on thetissue under treatment and also to adjust the level, the type of theelectrical stimuli, and/or any other suitable parameter to optimize thetreatment outcome. Using the drug delivery system, external orimplantable devices for drug delivery may also be controlled.

It should be noted that the delivery system of the present invention isalso capable of analyzing and/or controlling linear and non-linearprocesses, such as flow, pressure, temperature, and pH. For example, thedelivery system of the present invention may include an adaptivecontroller or a model free adaptive controller. In cases whereproportional-integral-derivative (PID) controllers may not be able tohandle large dynamic changes (e.g., the logarithmic changes of pH), themodel free adaptive controller may be used.

In some embodiments, the electrical stimulator component of the deliverysystem may be used to control the delivery of drugs, fluids, or othersubstances. Using the electrical stimulator component, several, simpleor complex rectangular pulses and other signals are available, for theoutput stages, through a selector or preferably on a bus. These signalsare synchronized and may be accessed by an output stage either byselecting only one signal or by accessing several signals at the sametime. In the latter case, the signals may be combined in the outputstage to a more complex pattern. In either case, they may be accessed bya single selected output stage or simultaneously by several, eitheridentical or different, output stages.

For example, the electrical stimulator component may include a signalgenerator that generates multiple signals, where each signal has acontrollable waveform based on one or more electrical parameters (e.g.,amplitude, frequency, shape, timing parameters, phase, pulse duration,and pulse repetition rate). The electrical stimulator component may alsoinclude a selection mechanism to select as output signals one or more ofthe signals generated by the signal generator. These output signals areplaced on one or more output terminals. For example, multiple signals(e.g., a combined signal) may be placed on a single output terminal. Inanother example, identical signals may be generated and placed ondifferent output terminals. In yet another example, different signalsmay be generated using the signal generator and placed on differentoutput terminals. The output signals control the release of thesubstance from the reservoirs connected to the delivery system.

It should be noted that the electrical stimulator is configurable suchthat the delivery of substances in reservoirs connected to the deliverysystem may be synchronized and/or preset (e.g., daily doses,intermittent, maintenance of treatment of a daily basis, etc.), fluidflow from reservoirs may be controlled such that precision mixture ofvarious substances (e.g., fluids or drugs) may be attained, substancesmay be time delayed or time released, substances may be volumetricallycontrolled, substances may be diluted to provide an appropriate dosage,etc. For example, the electrical stimulator may be configured togenerate two identical signals on different output ports that controlreservoirs containing different substances. Upon receiving the identicalsignals, the delivery system may synchronously dispense two differentsubstances at the same time.

Using the electrical stimulator component, the delivery system may beused for a number of applications when combined with different outputstages. The delivery system may be used as a controller in an automaticexternal or implantable drug delivery device. The delivery system may bepreset with predefined signal patterns for specific application or fordouble blind studies, thereby eliminating the need to continuouslydevelop new experimental systems at a larger cost.

The electrical stimulator component may be integrated in or connected toan external or implantable device that holds a given amount of drugs,fluids, or any other suitable substance (e.g., in one or morereservoirs). For example, electrodes that are connected to theelectrical stimulator component may be implanted in a tumor or placed inits immediate vicinity and current is caused to flow therethroughbetween the electrodes in the course of which a cytotoxic agent issynthesized in situ by a reaction between the material of the electrodeand a substance delivered to the tumor.

In practice those or other reactions may take place between theelectrode and the reagent introduced into the tumor, with a hollowelectrode or a catheter used for delivery, or between two or moresubstances either naturally occurring in the organism or introduced intothe tumor, with the electrode having an electrocatalytic effect. Thematerial of the electrode controls the course and/or the speed ofreactions whose products are cytotoxic.

One way of carrying out a method is by potential-controlled reaction atthe electrodes implanted in the tumor. Another way in accordance withthe invention is by using hollow electrodes or a catheter for adding anappropriate substance to ensure the proper chemical environment for theformation of the cytotoxic agent in situ. Still another way is bycontinuously or intermittently releasing in situ from an implantedreservoir (one embodiment is a hydrogel capsule, as described below)appropriate substances to ensure the proper chemical environment for theformation of the cytotoxic agent in situ. Such time released substances,activated electrically when needed, can be applied over extended periodsof time including a period after the main treatment has been completed,to prevent a reoccurrence of cancer. These can also be used to activatethe immune system response.

The same method can be used to produce in situ non-cytotoxic agents,which can later be converted to the cytotoxic agents by isomerization.Isomerization is a process whereby a compound is changed into one of itsisomers; i.e., one of two or more chemical substances having the sameelementary percentage composition and molecular weight but differing instructure, and therefore in properties. An example thereof istransplatin and cisplatin. While cisplatin is highly cytotoxic,transplatin is considered not to be.

Because the synthesis process is electrically-assisted and because theelectrical stimulator component is configurable (e.g., amplitude,frequency, shape, timing parameters, phase, pulse duration, and pulserepetition rate), the electrical stimulator component of the deliverysystem may be used to control the amount of cytotoxic agent, which issynthesized.

Additional systems and methods for in situ electrochemical treatment ofa malignant tumor, which destroys the tumor with minimal damage toregions surrounding the tumor, are described further in commonly-owned,commonly-assigned U.S. Pat. No. 6,708,066, which is hereby incorporatedby reference herein in its entirety.

In some embodiments, the delivery system of the present invention may beused to automatically control the release of various substances from adevice, such as an implantable device. For example, an implantablereservoir carrying one or more drugs, fluids, or other suitablesubstances may be automatically controlled by means of electricalmodulation of the material properties of the walls of such a reservoir,for example a hydrogel capsule, or by controlling a micro pump, e.g., aninsulin pump with an appropriate time sequence of an electric signal.

In some embodiments, the sensors used in the delivery system may behydrogel biosensors. Hydrogel biosensors (such as those developed byM-Biotech, Inc. of Salt Lake City, Utah) may be used for the continuousmonitoring of various substances, such as, for example, salt, pH,temperature, alcohol, amino acids, flavors, penicillin etc. Eachhydrogel biosensor generally consists of two parts: a hydrogel and aminiature pressure transducer. In case of a glucose biosensor, thehydrogel either swells or contracts as a function of glucoseconcentration changes in the body fluid. A pressure transducer is usedto measure the changes in the swelling of the hydrogel. A resultingvoltage signal (in mV) is produced on the output of the transducer.

In some embodiments, the sensors used in the delivery system may beself-assembling hydrogels or any other suitable self-assemblingsubstance. These self-assembling hydrogels may include two materials(e.g., fluids) that remain separate until, for example, a given pH levelis reached. Upon reaching that pH level, the two materials self-assembleinto a hydrogel. This pH-dependent hydrogel may also disassemble at aspecific pH level. These self-assembling hydrogels may be used asconfigurable membranes or reservoirs for drug delivery. For example,upon connecting the delivery system to control a self-assemblinghydrogel, the delivery system may be used to control the pH level of thehydrogel such that at a given pH (or other suitable parameter), thehydrogel assembles preventing and/or significantly reducing the amountof drugs or any suitable substance released to the area where thehydrogel is located. Similarly, a given pH may be attained such that thehydrogel dissembles at predefined pH and allows the drugs or anysuitable substance to be administered. The delivery system having theelectrical stimulator may be used to control the permeability of a givenarea or delivery port.

For example, a number of self-assembling hydrogel reservoirs may befabricated. Upon connecting each output port of the electricalstimulator component or any other suitable component to eachself-assembling hydrogel reservoir, the delivery system is capable ofcontrolling the release of each of the substances contained in eachreservoir (e.g., each reservoir contains 1 mL of a given drug and when 4mL of the drug are needed, four output signals are transmitted throughthe output ports to effect the release of four reservoirs).

In another suitable example, the reservoir may be made of any suitablematerial, where the reservoir has an opening (having a given dimension)made of the self-assembling hydrogel. For example, an electrode may beweaved through the self-assembling hydrogel such that the assembling anddisassembling of the hydrogel may be electrically controlled. Bycontrolling the hydrogel opening, the reservoir may release a givenamount of drugs for a predefined amount of time.

In the example of treating tissues, such as a malignant tumor, ahydrogel capsule may be used to continuously or intermittently releasein situ from an implanted reservoir appropriate substances, such asdrugs, to ensure the proper chemical environment for the formation ofthe cytotoxic agent in situ. Such time released substances, activatedelectrically when needed, may be applied over extended periods of timeincluding a period after the main treatment has been completed toprevent a reoccurrence of cancer.

Accordingly, in some embodiments, the delivery system may be used toautomatically adjust an electrical stimulation signal to optimize thetreatment outcome in response to receiving a specific parameter (e.g.,biomarker, time, volume, dosage, pH, etc.) measured over time.

It should be noted that the delivery system according to the presentinvention may include a general purpose computer, a specially programmedspecial purpose computer, or a microprocessor embedded in the system. Auser may interact with the system via e.g., a personal computer or overPDA, e.g., the Internet, an Intranet, or embedded web interface, etc.Either of these may be implemented as a distributed computer systemrather than a single computer. Similarly, the communications link may bea wireless link, a dedicated link, a modem over a POTS line, theInternet and/or any other method of communicating between computersand/or users. Moreover, the processing could be controlled by a softwareprogram on one or more computer systems or processors (e.g., without theelectrical stimulator component, etc.), or could even be partially orwholly implemented in hardware.

It should be noted that the resulting delivery system may be implementedas an electronic component that is optimized for size, cost andperformance and constitutes a main building block for various deliverydevices. Alternatively, the delivery system may also be available as anelectronic component with a sensor input and a feedback loop.

It is to be understood that the invention is not limited in itsapplication to the details of construction and to the arrangements ofthe components and systems set forth in the following description orillustrated in the drawings. The invention is capable of otherembodiments and of being practiced and carried out in various ways.Also, it is to be understood that the phraseology and terminologyemployed herein are for the purpose of description and should not beregarded as limiting.

As such, those skilled in the art will appreciate that the conception,upon which this disclosure is based, may readily be utilized as a basisfor the designing of other structures, methods and systems for carryingout the several purposes of the present invention. It is important,therefore, that the claims be regarded as including such equivalentconstructions insofar as they do not depart from the spirit and scope ofthe present invention.

Although the present invention has been described and illustrated in theforegoing exemplary embodiments, it is understood that the presentdisclosure has been made only by way of example, and that numerouschanges in the details of implementation of the invention may be madewithout departing from the spirit and scope of the invention, which islimited only by the claims which follow.

1. An apparatus for performing multiple diagnostics, the apparatuscomprising: a plurality of data acquisition modules that aresimultaneously available to a patient and connected to one or more dataprocessing modules, wherein the plurality of data acquisition modulessimultaneously obtain a plurality of data that includes at least one ofmeasurement data and biomarker data from a plurality of inputs andtransmit the obtained plurality of data that includes at least one ofmeasurement data and biomarker data relating to the patient to the oneor more data processing modules; a treatment output module connected toone or more of the one or more data processing modules that causes oneor more treatment regimens for the patient to be administered, whereinthe one or more treatment regimens for the patient are determined basedon the obtained data that includes at least one of measurement data andbiomarker data from the plurality of data acquisition modules; a usercontrol module connected to the one or more data processing modules; andwherein the one or more data processing modules generate patientinformation needed by the treatment output module.
 2. The apparatus ofclaim 1 further comprising: a user display system connected to the oneor more data processing modules, wherein the one or more data processingmodules being responsive to the user control module for generating thepatient information and for generating user display information for useby the user display system.
 3. The apparatus of claim 1, wherein theplurality of data acquisition modules sends the plurality of data thatincludes at least one of measurement data and biomarker data relating toa single disease to the one or more data processing modules.
 4. Theapparatus of claim 1, wherein the plurality of data acquisition modulessends the plurality of data that includes at least one of measurementdata and biomarker data relating to multiple diseases to the one or moredata processing modules.
 5. The apparatus of claim 1 further comprising:measuring modules, connected to the plurality of data acquisitionmodules, comprising one or more of: one or more biomarker sensors, a pHsensor, a pO₂ sensor, a spectrometer, an optical sensor, and anelectrical measurement system, a chemical measurement system, a physicalmeasurement system, and an electrochemical measurement system.
 6. Theapparatus of claim 1, wherein the plurality of data that includes atleast one of measurement data and biomarker data are received from atleast one of: a biosensor, a pH sensor, a pO₂ sensor, spectroscopy, anoptical sensor, an electrical measurement system, a chemical measurementsystem, a physical measurement system, and an electrochemicalmeasurement system.
 7. The apparatus of claim 6, wherein thespectroscopy is selected from at least one of: fluorescent spectroscopy,mass spectroscopy, Raman spectroscopy, and Fourier transform infraredspectroscopy.
 8. The apparatus of claim 1, further comprising acommunications module that communicates with an external database for atleast one of: receiving the patient information, receiving treatmentprotocols, receiving treatment information, storing the patientinformation, storing the treatment information, managing the patientinformation, managing the treatment information, and managing thetreatment.
 9. The apparatus of claim 8, wherein the communications areconducted using a secure protocol.
 10. The apparatus of claim 8, whereinthe external database provides at least a portion of the patientinformation and wherein the treatment output module uses the portion ofthe patient information for generating the treatment information. 11.The apparatus of claim 1, further comprising a wireless communicationsmodule that communicates with an external device.
 12. The apparatus ofclaim 11, wherein the wireless communications module is configured totransmit at least one of: the plurality of data, updated data, thepatient information, and the generated treatment information fordisplay.
 13. The apparatus of claim 11, wherein the wirelesscommunications module and the external device are configured to allow auser to manually control at least one of drug delivery, electricalsignal parameters, and treatment protocols.
 14. The apparatus of claim1, wherein each of the one of more data processing modules transmits theportion of the data to a single processing module for subsequentprocessing.
 15. The apparatus of claim 1, wherein the plurality of datais measured in real time and simultaneously.
 16. A method for performingmultiple diagnostics, the method comprising: simultaneously obtaining,using a plurality of data acquisition modules that are simultaneouslyavailable to a patient and connected to one or more data processingmodules, a plurality of data that includes at least one of measurementdata and biomarker data from a plurality of inputs; transmitting theobtained data that includes at least one of measurement data andbiomarker data relating to the patient to the one or more dataprocessing modules; in response to the obtained data that includes atleast one of measurement data and biomarker data, determining adiagnosis or treatment of a disease associated with the patient; andcausing one or more treatment regimens for the patient to beadministered based on the determined diagnosis or treatment, wherein theone or more treatment regimens for the patient are determined based onthe obtained data that includes at least one of measurement data andbiomarker data from the plurality of data acquisition modules.
 17. Themethod of claim 16, further comprising: selecting a plurality of theparameters to measure in response to a user input; and displaying to theuser, a diagnosis and a basis therefore.
 18. The method of claim 16,further comprising: in response to further measurements of theparameters, determining an effectiveness of the treatment, andmodifying, as necessary, the treatment regimen; and monitoring, on anon-going basis, the effectiveness of the treatment.
 19. The method ofclaim 16, further comprising: in response to the further measurements ofthe parameters, modifying, as necessary, the treatment regimen.
 20. Anapparatus for performing multiple diagnostics, the apparatus comprising:a data acquisition module that is available to a patient and that isconnected to a data processing module, wherein the data acquisitionmodule serially obtains, simultaneously in terms of body function, aplurality of data that includes at least one of measurement data andbiomarker data from one or more inputs and transmits the obtainedplurality of data that includes at least one of measurement data andbiomarker data relating to the patient to the data processing module; atreatment output module connected to the data processing module thatcauses one or more treatment regimens for the patient to beadministered, wherein the one or more treatment regimens for the patientare determined based on the obtained data that includes at least one ofmeasurement data and biomarker data from the data acquisition module; auser control module connected to the data processing module; and whereinthe data processing module generates patient information needed by thetreatment output module.